The research area is theme number 4, Focusing on Global Health. The broad goals of the project are to identify determinants of susceptibility and resistance to infection by HIV-1 subtype C and of disease progression among people severely affected by the HIV/AIDS epidemic in southern Africa, and to reduce the burden of HIV1-C infection by identifying host targets for developing new intervention and prevention strategies. Despite the worldwide predominance of HIV-1 subtype C (HIV-1C), most genome wide association studies (GWAS) have been conducted primarily on males of European ancestry infected by HIV-1 subtype B. The burden of HIV is greatest in southern Africa where the HIV-1C epidemic has infected 16% of adults of whom >60% are women, and the dominant mode of viral transmission is heterosexual. The proposed study represents the first GWAS for HIV-1C acquisition and control of viral replication, the first GWAS in the southern African population, and the first GWAS using the new 2.5 Illumina chip. Specific Aim 1: To perform a GWAS using the Illumina Omni 2.5 BeadChip on DNA samples from 3,200 HIV+ and 3,200 HIV- Tswana adults living in Gaborone, Botswana. Significant associations with HIV infection status and trajectories of viral load (VL) and CD4 levels from the GWAS will be replicated in a group of 5,500 HIV+ and 5,500 HIV- Tswana adults enrolled in the Mochudi HIV Treatment for Prevention Program. Specific Aim 2: To use whole-genome 30x sequencing for a subset of 6 individuals and exome sequencing for 77 (all with GWAS) representing extreme phenotypes for HIV-1C viral load to identify rare-to-moderate frequency variants. Functional genetic variation identified as putatively causal will be analyzed by association analysis in the full set of 17,400 individuals for association with HIV infection status and on 1,775 individuals for trajectories of VL and CD4+ T cells. Specific Aim 3: To use the results of the 1000 Genomes Project, phase three of the HapMap project, and our own deep sequencing of Tswana persons to identify causal variants that predict risk for HIV-1C infection status, and trajectories of VL and CD4+ counts. Coalescence-based analysis will be used to identify haplotypes harboring causal/functional SNPs. Putative causal SNPs will be genotyped on the entire group of 17,400 persons for association. This innovative study applies a GWAS combined with genome re-sequencing (30-fold) to the first southern African genetic study of HIV-1C infection. This is the first HIV GWAS powered for strong replication of results in an independent cohort. This study would identify novel host factors that may be targets for better understanding susceptibility and resistance to HIV infection and factors that determine the rate of disease progression. PUBLIC HEALTH RELEVANCE: This study is innovative in that it applies the Illumina 2.5 GWAS combined with deep sequencing to the first African genetic study of HIV-1C infection-plus this is the first HIV GWAS powered for strong replication and validation of results in independent subjects. This study is highly significant because it should identify novel host factors that may be targets for understanding resistance to initial infection and factors that determine the rate of progression. This study will also quantify the relative contribution of host genetic factors and non-genetic factors to the current epidemic in southern Africa.